Silvia Stacchiotti1, Stefano Ferrari2, Andres Redondo3, Nadia Hindi4, Emanuela Palmerini2, Maria Angeles Vaz Salgado5, Anna Maria Frezza6, Paolo Giovanni Casali7, Antonio Gutierrez8, Antonio Lopez-Pousa9, Giovanni Grignani10, Antoine Italiano11, Axel LeCesne12, Sarah Dumont12, Jean Yves Blay13, Nicolas Penel14, Daniel Bernabeu15, Enrique de Alava16, Marie Karanian17, Carlo Morosi18, Silvia Brich19, Gian Paolo Dagrada19, Viviana Vallacchi20, Chiara Castelli20, Monica Brenca21, Dominga Racanelli21, Roberta Maestro21, Paola Collini19, Josefina Cruz22, Javier Martin-Broto4. 1. Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. Electronic address: silvia.stacchiotti@istitutotumori.mi.it. 2. Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. 3. Department of Medical Oncology, University Hospital La Paz, Hospital La Paz Institute for Health Research, Madrid, Spain. 4. Department of Medical Oncology, University Hospital Virgen del Rocio, Seville, Spain; Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain. 5. Department of Medical Oncology, University Hospital Ramón y Cajal, Madrid, Spain. 6. Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. 7. Department of Cancer Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy; Department of Medical Oncology and Hemato-Oncology, University of Milan, Milan, Italy. 8. Hematology Department, University Hospital Son Espases, Palma, Illes Baleares, Spain. 9. Department of Medical Oncology, Sant Pau Hospital, Barcelona, Spain. 10. Division of Medical Oncology, Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia, IRCCS, Candiolo, Italy. 11. Department of Oncology, Institut Bergonié, Bordeaux, France. 12. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 13. Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France. 14. Medical Oncology Department, Centre Oscar Lambret, Lille, France. 15. Musculoskeletal Imaging Section, University Hospital La Paz, Hospital La Paz Institute for Health Research, Madrid, Spain. 16. Institute of Biomedicine of Sevilla, Universidad de Sevilla, Seville, Spain; Department of Pathology, University Hospital Virgen del Rocio, Seville, Spain. 17. Department of Pathology, Centre Léon Bérard, Lyon, France. 18. Department of Radiology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. 19. Department of Diagnostic Pathology and Laboratory Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. 20. Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy. 21. Oncogenetics and Oncogenomics Unit, Centro di Riferimento Oncologico di Aviano IRCCS, Aviano, Italy. 22. Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.
Abstract
BACKGROUND: Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma. METHODS: In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285. FINDINGS: Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]). INTERPRETATION: Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients. FUNDING: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
BACKGROUND:Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma. METHODS: In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285. FINDINGS: Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18-30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1-36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]). INTERPRETATION:Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients. FUNDING: Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
Authors: Anna Paioli; Silvia Stacchiotti; Domenico Campanacci; Emanuela Palmerini; Anna Maria Frezza; Alessandra Longhi; Stefano Radaelli; Davide Maria Donati; Giovanni Beltrami; Giuseppe Bianchi; Marta Barisella; Alberto Righi; Stefania Benini; Marco Fiore; Piero Picci; Alessandro Gronchi Journal: Ann Surg Oncol Date: 2020-06-22 Impact factor: 5.344
Authors: Benedetta Chiusole; Axel Le Cesne; Marco Rastrelli; Marco Maruzzo; Martina Lorenzi; Rocco Cappellesso; Paolo Del Fiore; Silvia Imbevaro; Marta Sbaraglia; Philippe Terrier; Pietro Ruggieri; Angelo Paolo Dei Tos; Carlo Riccardo Rossi; Vittorina Zagonel; Antonella Brunello Journal: Front Oncol Date: 2020-06-16 Impact factor: 6.244
Authors: Sara Velayati; Joseph P Erinjeri; Lynn A Brody; Etay Ziv; Franz E Boas; Karen T Brown; Anne M Covey; George I Getrajdman; Stephen B Solomon; Peter T Kingham; William D Tap; William R Jarnagin; Hooman Yarmohammadi Journal: Sarcoma Date: 2019-09-03